Substituted 2-pyridine cyclohexane-1,4-diamine compounds

ABSTRACT

Substituted 2-pyridine cyclohexane-1,4-diamine compounds, a method for their production, pharmaceutical compositions containing them, and the use of such substituted 2-pyridine cyclohexane-1,4-diamine compounds for treating pain and various other medical conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of international patentapplication no. PCT/EP02/05078, filed May 8, 2002, designating theUnited States of America, and published in German as WO 02/090330, theentire disclosure of which is incorporated herein by reference. Priorityis claimed based on Federal Republic of Germany patent application no.DE 101 23 163.6, filed May 9, 2001.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to substituted 2-pyridinecyclohexane-1,4-diamine compounds, to a process for their production,pharmaceutical compositions containing these compounds and totherapeutic uses of substituted 2-pyridine cyclohexane-1,4-diaminecompounds.

[0003] The heptadecapeptide nociceptin is an endogenous ligand of theORL1 (opioid receptor-like) receptor (Meunier et al., Nature 377, 1995,p. 532-535), which belongs to the family of opioid receptors and can befound in many regions of the brain and spinal cord (Mollereau et al.,FEBS Letters, 341, 1994, p. 33-38, Darland et al., Trends inNeurosciences, 21, 1998, p. 215-221). The peptide is characterised by ahigh affinity, with a K_(d) value of approximately 56 pM (Ardati et al.,Mol. Pharmacol. 51, p. 816-824), and by a high selectivity for the ORL1receptor. The ORL1 receptor is homologous to the μ, κ and δ opioidreceptors and the amino acid sequence of the nociceptin peptide displaysa strong similarity to those of the known opioid peptides. Thenociceptin-induced activation of the receptor, via coupling with G_(i/o)proteins, leads to an inhibition of adenylate cyclase (Meunier et al.,Nature 377, 1995, p. 532-535). On a cellular level too there arefunctional similarities between the μ, κ and δ opioid receptors and theORL1 receptor with regard to the activation of the potassium channel(Matthes et al., Mol. Pharmacol. 50, 1996, p. 447-450; Vaughan et al.,Br. J. Pharmacol. 117, 1996, p. 1609-1611) and the inhibition of the L,N and P/Q type calcium channels (Conner et al., Br. J. Pharmacol. 118,1996, p. 205-207; Knoflach et al., J. Neuroscience 16, 1996, p.6657-6664).

[0004] After intracerebroventicular administration the nociceptinpeptide displays a pronociceptive and hyperalgesic activity in variousanimal models (Reinscheid et al., Science 270, 1995, p. 792-794; Hara etal., Br. J. Pharmacol. 121, 1997, p. 401-408). These findings can beexplained as inhibition of stress-induced analgesia (Mogil et al.,Neurosci. Letters 214, 1996, p. 131-134; and Neuroscience 75, 1996, p.333-337). In this connection an anxiolytic activity of nociceptin hasalso been demonstrated (Jenck et al., Proc. Natl. Acad. Sci. USA 94,1997, 14854-14858).

[0005] On the other hand, an antinociceptive effect of nociceptin hasalso been demonstrated in various animal models, particularly afterintrathecal administration. Nociceptin inhibits the activity of kainate-or glutamate-stimulated basal ganglia neurones (Shu et al.,Neuropeptides, 32, 1998, 567-571) or glutamate-stimulated spinal cordneurones (Faber et al., Br. J. Pharmacol., 119, 1996, p. 189-190); ithas an antinociceptive action in the tail flick test in mice (King etal., Neurosci. Lett., 223, 1997, 113-116), in the flexor reflex model inrats (Xu et al., NeuroReport, 7, 1996, 2092-2094) and in the formalintest in rats (Yamamoto et al., Neuroscience, 81, 1997, p. 249-254). Anantinociceptive action of nociceptin has also been demonstrated inmodels for neuropathic pain (Yamamoto and Nozaki-Taguchi,Anesthesiology, 87, 1997), which is particularly interesting in as muchas the activity of nociceptin increases after axotomy of the spinalnerves. This is in contrast to the classical opioids, whose activitydecreases under these conditions (Abdulla and Smith, J. Neurosci., 18,1998, p. 9685-9694).

[0006] Furthermore, the ORL1 receptor is also involved in the regulationof other physiological and pathophysiological processes. These includeamong others learning and memory development (Sandin et al., Eur. J.Neurosci., 9, 1997, p. 194-197; Manabe et al., Nature, 394, 1997, p.577-581), hearing (Nishi et al., EMBO J., 16, 1997, p. 1858-1864),eating (Pomonis et al., NeuroReport, 8, 1996, p. 369-371), bloodpressure regulation (Gumusel et al., Life Sci., 60, 1997, p. 141-145;Campion and Kadowitz, Biochem. Biophys. Res. Comm., 234, 1997, p.309-312), epilepsy (Gutierrez et al., Abstract 536.18, Society forNeuroscience, Vol. 24, 28^(th) Ann. Meeting, Los Angeles, Nov. 7-12,1998) and diuresis (Kapista et al., Life Sciences, 60, 1997, PL 15-21).An overview article by Calo et al. (Br. J. Pharmacol., 129, 2000,1261-1283) gives an overview of the indications or biological processesin which the ORL1 receptor plays or with a high degree of probabilitycould play a part. Those cited include: analgesia, stimulation andregulation of eating, influence on μ-agonists such as morphine,treatment of withdrawal symptoms, reduction of the addiction potentialof morphines, anxiolysis, modulation of motor activity, amnesia,epilepsy; modulation of neurotransmitter release, particularly ofglutamate, serotonin and dopamine, and hence neurodegenerative diseases;influencing of the cardiovascular system, triggering of an erection,diuresis, antinatriuresis, ionic equilibrium, aterial blood pressure,water-storage disorders, intestinal motility (diarrhoea), relaxingeffects on the respiratory tracts, micturation reflex (urinaryincontinence). The use of agonists and antagonists as anoretics,analgesics (also in coadministration with opioids) or nootropics is alsodiscussed.

[0007] The possible applications of compounds that bind to the ORL1receptor and activate or inhibit it are correspondingly diverse.

SUMMARY OF THE INVENTION

[0008] The object of the present invention was to provide medicamentsthat act on the nociceptin/ORL1 receptor system and are thereforesuitable as medicaments for the treatment of, in particular, the variousdiseases known in the art to be linked with this system or for treatingindications associated with this receptor system.

[0009] The invention thus provides substituted 2-pyridinecyclohexane-1,4-diamine compounds corresponding to the formula I,

[0010] wherein

[0011] R¹ and R² are independently selected from H; C₁₋₈ alkyl or C₃₋₈cycloalkyl, each being saturated or unsaturated, branched or unbranched,mono- or polysubstituted or unsubstituted; aryl or heteroaryl, eachbeing mono- or polysubstituted or unsubstituted; or aryl, C₃₋₈cycloalkyl or heteroaryl bonded via C₁₋₃ alkylene, each being mono- orpolysubstituted or unsubstituted;

[0012] or the radicals R¹ and R² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂ or (CH₂)₃₋₆,

[0013] where R⁶ is selected from H; C₁₋₈ alkyl or C₃₋₈ cycloalkyl, eachbeing saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; aryl or heteroaryl, each being mono-or polysubstituted or unsubstituted; or aryl, C₃₋₈ cycloalkyl orheteroaryl bonded via C₁₋₃ alkylene, each being mono- or polysubstitutedor unsubstituted;

[0014] R³ is selected from H; C₁₋₈ alkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; C₃₋₈ cycloalkyl, saturated or unsaturated, mono- orpolysubstituted or unsubstituted; aryl or heteroaryl, each being mono-or polysubstituted or unsubstituted; or aryl, C₃₋₈ cycloalkyl orheteroaryl bonded via C₁₋₃ alkylene, each being mono- or polysubstitutedor unsubstituted; SH, OH, F, Cl, I, Br, CN, NO₂, OR²⁶, NR²⁷R²⁸;

[0015] where R²⁶ is selected from C₁₋₆ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; C₃₋₈cycloalkyl, saturated or unsaturated, mono- or polysubstituted orunsubstituted; aryl or heteroaryl, each being unsubstituted or mono- orpolysubstituted with F, Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅,C₃H₇, C₄H₉, OCF₃, OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and/or OH;aryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃ alkyl, saturated orunsaturated, each being unsubstituted or mono- or polysubstituted withF, Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃,OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and/or OH;

[0016] where R²⁷ and R²⁸ are independently selected from H, C₁₋₆ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; C₃₋₈ cycloalkyl, saturated orunsaturated, mono- or polysubstituted or unsubstituted; aryl orheteroaryl, each being unsubstituted or mono- or polysubstituted with F,Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃,OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and/or OH; aryl, C₃₋₈cycloalkyl or heteroaryl bonded via C₁₋₃ alkyl, saturated orunsaturated, each being unsubstituted or mono- or polysubstituted withF, Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃,OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and/or OH;

[0017] or the radicals R²⁷ and R²⁸ together denote CH₂CH₂OCH₂CH₂,CH₂CH₂NR²⁹CH₂CH₂ or (CH₂)₃₋₆, where

[0018] R²⁹ is selected from H, C₁₋₆ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; C₃₋₈cycloalkyl, saturated or unsaturated, mono- or polysubstituted orunsubstituted; aryl or heteroaryl, each being unsubstituted or mono- orpolysubstituted with F, Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅,C₃H₇, C₄H₉, OCF₃, OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and/or OH;aryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃ alkyl, saturated orunsaturated, each being unsubstituted or mono- or polysubstituted withF, Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃,OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and/or OH;

[0019] R⁴ is selected from H, C₁₋₈ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; orC(X)R⁷, C(X)NR⁷R⁸, C(X)OR⁹, C(X)SR⁹, S(O₂) R⁹

[0020] where X═O or S,

[0021] where R⁷ is selected from H, C₁₋₈ alkyl or C₃₋₈ cycloalkyl, eachbeing saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; aryl, heteroaryl, each beingunsubstituted or mono- or polysubstituted; aryl, C₃₋₈ cycloalkyl orheteroaryl bonded via a saturated or unsaturated, branched orunbranched, substituted or unsubstituted C₁₋₄ alkyl group, each beingunsubstituted or mono- or polysubstituted;

[0022] where R⁸ is selected from H, C₁₋₄ alkyl, saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted or

[0023] the radicals R⁷ and R⁸ together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆,

[0024] where R¹⁰ is selected from H; C₁₋₈ alkyl or C₃₋₈ cycloalkyl, eachbeing saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; aryl or heteroaryl, each being mono-or polysubstituted or unsubstituted; or aryl, C₃₋₈ cycloalkyl orheteroaryl bonded via C₁₋₃ alkylene, each being mono- or polysubstitutedor unsubstituted;

[0025] where R⁹ is selected from C₁₋₈ alkyl or C₃₋₈ cycloalkyl, eachbeing saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; aryl, heteroaryl, each beingunsubstituted or mono- or polysubstituted; aryl, C₃₋₈ cycloalkyl orheteroaryl bonded via a saturated or unsaturated, branched orunbranched, substituted or unsubstituted C₁₋₄ alkyl group, each beingunsubstituted or mono- or polysubstituted;

[0026] R⁵ is selected from C₃₋₈ cycloalkyl, aryl or heteroaryl, eachbeing unsubstituted or mono- or polysubstituted; —CHR¹¹R¹²,—CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹²,—C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹² or —C(Y)—CH₂—CH₂—CH₂R¹²

[0027] where Y═O, S or H₂,

[0028] where R¹¹ is selected from

[0029] H, C₁₋₇ alkyl, saturated or unsaturated, branched or unbranched,mono- or polysubstituted or unsubstituted; or C(O)O—C₁₋₆ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0030] and where R¹² is selected from

[0031] H; C₃₋₈ cycloalkyl, aryl or heteroaryl, each being unsubstitutedor mono- or polysubstituted,

[0032] or R⁴ and R⁵ together form a heterocyclic compound with between 3and 8 atoms in the ring, saturated or unsaturated; mono- orpolysubstituted or unsubstituted, which can optionally be condensed withother rings,

[0033] optionally in the form of their racemates, their purestereoisomers, in particular enantiomers or diastereomers, or in theform of mixtures of stereoisomers, in particular enantiomers ordiastereomers, in any mixing ratio;

[0034] in the form described or in the form of their acids or theirbases or in the form of their salts, in particular the physiologicallycompatible salts or salts of physiologically compatible acids orcations; or in the form of their solvates, in particular hydrates.

[0035] All these compounds or groups of compounds according to theinvention display outstanding binding to the ORL1 receptor.

[0036] Within the meaning of this invention alkyl or cycloalkyl radicalsare understood to be saturated and unsaturated (but not aromatic),branched, unbranched and cyclic hydrocarbons, which can be unsubstitutedor mono- or polysubstituted. C₁₋₂ alkyl stands for C1 or C2 alkyl, C₁₋₃alkyl for C1, C2 or C3 alkyl, C₁₋₄ alkyl for C1, C2, C3 or C4 alkyl,C₁₋₅ alkyl for C1, C2, C3, C4 or C5 alkyl, C₁₋₆ alkyl for C1, C2, C3,C4, C5 or C6 alkyl, C₁₋₇ alkyl for C1, C2, C3, C4, C5, C6 or C7 alkyl,C₁₋₈ alkyl for C1, C2, C3, C4, C5, C6, C7 or C8 alkyl, C₁₋₁₀ alkyl forC1, C2, C3, C4, C5, C6, C7, C8, C9 or C₁₀ alkyl and C₁₋₁₈ alkyl for C1,C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17or C₁₋₈ alkyl. Further, C₃₋₄ cycloalkyl stands for C3 or C4 cycloalkyl,C₃₋₅ cycloalkyl for C3, C4 or C5 cycloalkyl, C₃₋₆ cycloalkyl for C3, C4,C5 or C6 cycloalkyl, C₃₋₇ cycloalkyl for C3, C4, C5, C6 or C7cycloalkyl, C₃₋₈ cycloalkyl for C3, C4, C5, C6, C7 or C8 cycloalkyl,C₄₋₅ cycloalkyl for C4 or C5 cycloalkyl, C₄₋₆ cycloalkyl for C4, C5 orC6 cycloalkyl, C₄₋₇ cycloalkyl for C4, C5, C6 or C7 cycloalkyl, CS-₆cycloalkyl for C5 or C6 cycloalkyl and C₅₋₇ cycloalkyl for C5, C6 or C7cycloalkyl. With regard to cycloalkyl, the term also includes saturatedcycloalkyls, in which one or 2 carbon atoms are replaced by aheteroatom, S, N or O. However, the term cycloalkyl also includes inparticular mono- or polyunsaturated, preferably monounsaturatedcycloalkyls with no heteroatom in the ring, provided that the cycloalkylis not an aromatic system. The alkyl or cycloalkyl radicals arepreferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl),1-propynyl, methyl ethyl, butyl, 1-methyl propyl, 2-methyl propyl,1,1-dimethyl ethyl, pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl,2,2-dimethyl propyl, hexyl, 1-methyl pentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropyl methyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF₂,CF₃ or CH₂OH and pyrazolinone, oxopyrazolinone, [1,4]dioxan ordioxolane.

[0037] In connection with alkyl and cycloalkyl, within the meaning ofthis invention the term substituted—unless expressly definedotherwise—refers to the substitution of at least one (optionally alsoseveral) hydrogen radicals by F, Cl, Br, I, NH₂, SH or OH,“polysubstituted” or “substituted” in the case of multiple substitutionmeaning that substitution takes place more than once both at differentand also at the same atoms with the same or different substituents, forexample three times at the same C atom as in the case of CF₃ or atvarious sites as in the case of —CH(OH)—CH═CH—CHCl₂. Particularlypreferred substituents in this context are F, Cl and OH. With regard tocycloalkyl the hydrogen radical can also be replaced by OC₁₋₃ alkyl orC₁₋₃ alkyl (each being mono- or polysubstituted or unsubstituted), inparticular methyl, ethyl, n-propyl, i-propyl, CF₃, methoxy or ethoxy.

[0038] The term (CH₂)₃₋₆ means —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂— and CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, (CH₂)₁₋₄ means—CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—, (CH₂)₄₋₅ means—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—, etc.

[0039] An aryl radical refers to ring systems with at least one aromaticring but without heteroatoms in even just one of the rings. Examplesinclude phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl orindanyl, in particular 9H-fluorenyl or anthracenyl radicals, which canbe unsubstituted or mono- or polysubstituted.

[0040] A heteroaryl radical refers to heterocyclic ring systems with atleast one unsaturated ring, which contain one or more heteroatomsselected from the group consisting of nitrogen, oxygen and/or sulfur andcan also be mono- or polysubstituted. From the group of heteroaryls,furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine,benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole,benzodioxolane, benzodioxan, carbazole, indol and quinazoline can becited by way of example.

[0041] In connection with aryl and heteroaryl the term substitutedrefers to substitution of the aryl or heteroaryl with R²², OR²², ahalogen, preferably F and/or Cl, a CF₃, a CN, an NO₂, an NR²³R², a C₁₋₆alkyl (saturated), a C₁₋₆ alkoxy, a C₃₋₈ cycloalkoxy, a C₃₋₈ cycloalkylor a C₂₋₆ alkylene.

[0042] In this context the radical R²² stands for H, a C₁₋₁₀ alkyl,preferably a C₁₋₆ alkyl, an aryl or heteroaryl or for an aryl orheteroaryl radical bonded via C₁₋₃ alkyl, saturated or unsaturated, orvia a C₁₋₃ alkylene group, wherein these aryl and heteroaryl radicalsmay not themselves be substituted with aryl or heteroaryl radicals,

[0043] the radicals R²³ and R²⁴, which are the same or different, denoteH, a C₁₋₁₀ alkyl, preferably a C₁₋₆ alkyl, an aryl, a heteroaryl or anaryl or heteroaryl radical bonded via C₁₋₃ alkyl, saturated orunsaturated, or via a C₁₋₃ alkylene group, wherein these aryl andheteroaryl radicals may not themselves be substituted with aryl orheteroaryl radicals,

[0044] or the radicals R²³ and R²⁴ together denote CH₂CH₂OCH₂CH₂,CH₂CH₂NR²CH₂CH₂ or (CH₂)₃₋₆, and

[0045] the radical R²⁵ stands for H, a C₁₋₁₀ alkyl, preferably a C₁₋₆alkyl, an aryl or heteroaryl radical or for an aryl or heteroarylradical bonded via C₁₋₃ alkyl, saturated or unsaturated, or via a C₁₋₃alkylene group, wherein these aryl and heteroaryl radicals may notthemselves be substituted with aryl or heteroaryl radicals.

[0046] The term salt refers to any form of the active ingredientaccording to the invention in which it assumes an ionic form or ischarged and is coupled with a counterion (a cation or anion) or is insolution. This also includes complexes of the active ingredient withother molecules and ions, in particular complexes that are complexed viaionic interactions. In particular (and this is also a preferredembodiment of this invention) it refers to physiologically compatiblesalts, particularly physiologically compatible salts with cations orbases and physiologically compatible salts with anions or acids or asalt formed with a physiologically compatible acid or a physiologicallycompatible cation.

[0047] Within the meaning of this invention the term “physiologicallycompatible salt with anions or acids” is understood to mean salts of atleast one of the compounds according to the invention—generallyprotonated, for example on nitrogen—as a cation with at least one anion,which are physiologically—particularly in applications in humans and/ormammals—compatible. Within the meaning of this invention this isunderstood to mean in particular the salt formed with a physiologicallycompatible acid, namely salts of the particular active ingredient withinorganic or organic acids which are physiologically—particularly inapplications in humans and/or mammals—compatible. Examples ofphysiologically compatible salts of specific acids are salts of:hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonicacid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid,tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid,glutamic acid, 1,1-dioxo-1,2-dihydrolb6-benzo[d]isothiazol-3-one(saccharinic acid), monomethyl sebacic acid, 5-oxoproline,hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid,2,4,6-trimethyl benzoic acid, a-liponic acid, acetyl glycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The hydrochloridesalt is particularly preferred.

[0048] Within the meaning of this invention the term “salt formed with aphysiologically compatible acid” is understood to mean salts of theparticular active ingredient with inorganic or organic acids which arephysiologically—particularly in applications in humans and/ormammals—compatible. Hydrochloride is particularly preferred. Examples ofphysiologically compatible acids are: hydrochloric acid, hydrobromicacid, sulfuric acid, methane sulfonic acid, formic acid, acetic acid,oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid,lactic acid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro1λ⁶-benzo[d] isothiazol-3-one (saccharinic acid),monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl benzoic acid,α-liponic acid, acetyl glycine, acetyl salicylic acid, hippuric acidand/or aspartic acid.

[0049] Within the meaning of this invention the term “physiologicallycompatible salt with cations or bases” is understood to mean salts of atleast one of the compounds according to the invention—generally a(deprotonated) acid—as anion with at least one, preferably inorganic,cation, which are physiologically—particularly in applications in humansand/or mammals—compatible. Particularly preferred are the salts ofalkali and alkaline-earth metals but also NH₄ ⁺, but particularly(mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium orcalcium salts.

[0050] Within the meaning of this invention the term “salt formed with aphysiologically compatible cation” is understood to mean at least one ofthe relevant compounds as anion with at least one inorganic cation,which is physiologically —particularly in applications in humans and/ormammals —compatible. Particularly preferred are the salts of alkali andalkaline earth metals but also NH₄ ⁺, but particularly (mono-) or (di-)sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

[0051] In one preferred embodiment the substituted 2-pyridinecyclohexane-1,4-diamine compounds are synthesised in such a way thataccording to formula I

[0052] R¹ and R² are independently selected from H; C₁₋₈ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0053] or the radicals R¹ and R² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂ or (CH₂)₃₆,

[0054] where R⁶ is selected from H; C₁₋₈ alkyl, saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted,

[0055] preferably

[0056] R¹ and R² are independently selected from H; C₁₋₄ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0057] or the radicals R¹ and R² together form a ring and denote(CH₂)₄₋₅,

[0058] in particular

[0059] R¹ and R² are independently selected from methyl or ethyl or theradicals R¹ and R² together form a ring and denote (CH₂)₅.

[0060] In a preferred embodiment the substituted 2-pyridinecyclohexane-1,4-diamine compounds are synthesised in such a way thataccording to formula I

[0061] R³ is selected from H; C₁₋₈ alkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; C₃₋₈ cycloalkyl, saturated or unsaturated, mono-orpolysubstituted or unsubstituted; aryl or heteroaryl, each being mono-or polysubstituted or unsubstituted; or aryl, C₃₋₈ cycloalkyl orheteroaryl bonded via C₁₋₃ alkylene, each being mono- or polysubstitutedor unsubstituted; SH, OH, F, Cl, I, Br, CN, NO₂, NH₂, OR²⁶

[0062] where R²⁶ is selected from C₁₋₆ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted;

[0063] preferably

[0064] R³ is selected from H; C₁₋₆ alkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; SH, OH, F, Cl, I, Br, CN, NO₂, NH₂, OR²⁶;

[0065] where R²⁶ is selected from C₁₋₆ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted;

[0066] in particular

[0067] R³ is selected from H.

[0068] In another preferred embodiment the substituted 2-pyridinecyclohexane-1,4-diamine compounds are synthesised in such a way thataccording to formula I

[0069] R⁴ is selected from H, C(X)R⁷, C(X)NR⁷R⁸, C(X)OR⁹, C(X)SR⁹ orS(O₂)R⁹ where X═O or S,

[0070] preferably

[0071] R⁴ is selected from H, C(X)R⁷, C(X)NR⁷R⁸ or C(X)OR⁹ where X═O,

[0072] in particular

[0073] R⁴ is selected from H or C(O)R⁷; preferably with R⁷ selected from

[0074] H; or C₁₋₈ alkyl, saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted;

[0075] preferably

[0076] H; or C₁₋₃ alkyl, saturated, unsubstituted, branched orunbranched;

[0077] in particular CH₃.

[0078] In a further preferred embodiment the substituted 2-pyridinecyclohexane-1,4-diamine compounds are synthesised in such a way thataccording to formula I

[0079] R⁴ and R⁵ together form a heterocyclic compound with between 3and 8 atoms in the ring, saturated or unsaturated; mono- orpolysubstituted or unsubstituted, preferably with between 5 and 7 atomsin the ring, of which in addition to the obligatory N, 0 to 1 otherheteroatoms, selected from N, S or O, are in the ring;

[0080] wherein the heterocyclic compound formed by R⁴ and R⁵ togethercan optionally be condensed with other rings,

[0081] preferably with aromatic and/or heteroaromatic rings, whereinthese can be condensed with other aromatic and/or heteroaromatic rings,

[0082] in particular the heterocyclic compound formed by R⁴ and R⁵together is condensed with one or two other rings,

[0083] the heterocyclic compound formed by R⁴ and R⁵ together ispreferably condensed with two other rings in such a way that R⁴ and R⁵together denote

[0084] In yet another preferred embodiment the substituted 2-pyridinecyclohexane-1,4-diamine compounds are synthesised in such a way thataccording to formula I

[0085] R⁴ is selected from H or C₁₋₈ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted,

[0086] preferably

[0087] H or C₁₋₆ alkyl, saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted,

[0088] in particular

[0089] H or C₁₋₃ alkyl, saturated, unbranched and unsubstituted.

[0090] In a still further preferred embodiment the substituted2-pyridine cyclohexane-1,4-diamine compounds are synthesised in such away that according to formula I

[0091] R⁵ is selected from C₃₋₈ cycloalkyl, aryl or heteroaryl, eachbeing unsubstituted or mono- or polysubstituted;

[0092] preferably

[0093] R⁵ is selected from cyclobutyl, cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl,benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl,acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl,pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl,benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl,pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl,dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl,phthalazinyl or quinazolinyl, each being unsubstituted or mono- orpolysubstituted;

[0094] in particular

[0095] R⁵ is selected from cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl,benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl,carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl orpyrimidyl, each being unsubstituted or mono- or polysubstituted.

[0096] In a further particularly preferred embodiment the substituted2-pyridine cyclohexane-1,4-diamine compounds are synthesised in such away that according to formula I

[0097] R⁵ is selected from —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹²,—CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R, —C (Y)-CH₂R —C(Y)—CH₂—CH₂R¹² or—C(Y)—CH₂—CH₂—CH₂R¹²

[0098] where Y═O, S or H₂,

[0099] preferably

[0100] R⁵ is selected from —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹²,—C(Y)R¹², —C(Y)—CH₂R¹² or —C(Y)—CH₂—CH₂R¹²

[0101] where Y═O or S,

[0102] in particular

[0103] R⁵ is selected from —CHR¹¹R¹² ₁—CHR¹¹—CH₂R¹²—CHR¹¹—CH₂—CH₂R¹²,—C(Y)R¹² or —C(Y)—OH₂R¹²

[0104] where Y═O.

[0105] With regard to this embodiment it is particularly preferable if

[0106] R¹¹ is selected from

[0107] H, C₁₋₄ alkyl, saturated or unsaturated, branched or unbranched,mono- or polysubstituted or unsubstituted; or C(O)0-C₁₋₄ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0108] preferably

[0109] H, C₁₋₄ alkyl, saturated or unsaturated, branched or unbranched,mono- or polysubstituted or unsubstituted; or C(O)O—C₁₋₂ alkyl,saturated, unbranched, mono- or polysubstituted or unsubstituted;

[0110] in particular

[0111] H, CH₃, C₂H₅ and C(O)O—CH₃

[0112] and/or it is just as particularly preferable if

[0113] R¹² is selected from C₃₋₈ cycloalkyl, aryl or heteroaryl, eachbeing unsubstituted or mono- or polysubstituted;

[0114] preferably

[0115] R¹² is selected from cyclobutyl, cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl,benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl,acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl,pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl,benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl,pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl,dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl,phthalazinyl or quinazolinyl, each being unsubstituted or mono- orpolysubstituted;

[0116] in particular

[0117] R¹² is selected from cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl,benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl,carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl orpyrimidyl, each being unsubstituted or mono- or polysubstituted.

[0118] Furthermore the substituted 2-pyridine cyclohexane-1,4-diaminecompounds according to the invention are particularly preferablyselected from the following group:

[0119] N-(4-dimethylamino-4-pyridin-2-ylcyclohexyl)-N-[2-(1H-indol-3-yl)ethyl] acetamide dihydrochloride,non-polar diastereoisomer

[0120] N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride, non-polar diastereoisomer

[0121] N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride, polar diastereoisomer

[0122] (S)-2-(4-dimethylamino-4-pyridin-2-ylcyclohexylamino)-3-(1H-indol-3-yl) methyl propionate trihydrochloride,non-polar diastereoisomer

[0123] (S)-2-(4-dimethylamino-4-pyridin-2-ylcyclohexylamino)-3-(1H-indol-3-yl) methyl propionate trihydrochloride,polar diastereoisomer

[0124] (S)-2-(4-dimethylamino-4-pyridin-2-ylcyclohexylamino)-3-(1H-indol-3-yl) propionic acid dihydrochloride,non-polar diastereoisomer,

[0125] optionally also in the form of their racemates, the cited orother pure stereoisomers, in particular enantiomers or diastereomers, orin the form of mixtures of stereoisomers, in particular enantiomers ordiastereomers, in any mixing ratio;

[0126] optionally also in the form of acids or bases or in the form ofother salts, particularly physiologically compatible salts or salts ofphysiologically compatible acids or cations; or in the form of theirsolvates, in particular hydrates.

[0127] The substances according to the invention are non-toxic, so theyare suitable as a pharmaceutical active ingredient in medicaments.

[0128] The invention therefore also provides pharmaceutical compositionscontaining at least one substituted 2-pyridine cyclohexane-1,4-diaminecompound according to the invention, optionally in the form of itsracemate, pure stereoisomers, in particular enantiomers ordiastereomers, or in the form of mixtures of stereoisomers, inparticular enantiomers or diastereomers, in any mixing ratio; in theform described or in the form of its acids or its bases or in the formof its salts, in particular the physiologically compatible salts orsalts of physiologically compatible acids or cations; or in the form ofits solvates, in particular hydrates, and optionally containing suitableadditives and/or auxiliary substances and/or optionally other activeingredients.

[0129] In addition to at least one substituted 2-pyridinecyclohexane-1,4-diamine compound according to the invention, themedicaments according to the invention optionally contain suitableadditives and/or auxiliary substances, such as supporting materials,fillers, solvents, diluents, dyes and/or binders and can be administeredas liquid dosage forms in the form of injection solutions, drops orlinctuses, as semi-solid dosage forms in the form of granules, tablets,pellets, patches, capsules, plasters or aerosols. The choice ofauxiliary substances, etc., and the amounts of them to be used depend onwhether the medicament is to be administered by the oral, peroral,parenteral, intravenous, intraperitoneal, intradermal, intramuscular,intranasal, buccal or rectal route or locally, for example onto theskin, the mucous membranes or into the eyes. Preparations in the form oftablets, pastilles, capsules, granules, drops, linctuses and syrups aresuitable for oral administration, solutions, suspensions, readilyreconstitutable dry preparations and sprays for parenteral, topical andinhalative administration. Substituted 2-pyridinecyclohexane-1,4-diamine compounds according to the invention in a depotinjection, in dissolved form or in a plaster, optionally with additionof agents promoting skin penetration, are preparations that are suitablefor percutaneous administration. Preparation forms that can be used fororal or percutaneous administration can release the substituted2-pyridine cyclohexane-1,4-diamine compounds according to the inventionon a delayed basis. In principle other additional active ingredientsknown to the person skilled in the art can be added to thepharmaceutical compositions of the invention.

[0130] The amount of active ingredient to be administered to the patientvaries according to the weight of the patient, the form ofadministration, the indication and the severity of the disease.Conventionally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg, of atleast one substituted 2-pyridine cyclohexane-1,4-diamine compoundaccording to the invention is administered.

[0131] For all above forms of the pharmaceutical compositions accordingto the invention, it is particularly preferable if in addition to atleast one substituted 2-pyridine cyclohexane-1,4-diamine compound thepharmaceutical composition also contains an opioid, preferably a strongopioid, in particular morphine, or an anaesthetic, preferablyhexobarbital or halothane.

[0132] In a preferred form of the pharmaceutical composition, asubstituted 2-pyridine cyclohexane-1,4-diamine compound according to theinvention contained therein is present as a pure diastereomer and/orenantiomer, as a racemate or as a non-equimolar or equimolar mixture ofdiastereomers and/or enantiomers.

[0133] As can be read in the introduction with regard to the prior art,the ORL1 receptor has been identified in particular in the occurrence ofpain. Accordingly, substituted 2-pyridine cyclohexane-1,4-diaminecompounds according to the invention can be used for the treatment ofpain, in particular of acute, neuropathic or chronic pain.

[0134] The invention therefore also embraces the use of substituted2-pyridine cyclohexane-1,4-diamine compounds according to the invention;optionally in the form of their racemates, their pure stereoisomers, inparticular enantiomers or diastereomers, or in the form of mixtures ofstereoisomers, in particular enantiomers or diastereomers, in any mixingratio; in the form described or in the form of their acids or theirbases or in the form of their salts, in particular the physiologicallycompatible salts or salts of physiologically compatible acids orcations; or in the form of their solvates, in particular hydrates; forthe treatment of pain, in particular of acute, neuropathic or chronicpain.

[0135] As already noted above, in addition to its function in theoccurrence of pain the ORL1 receptor also plays a role in many otherphysiological processes of medical relevance in particular, so theinvention also embraces the use of substituted 2-pyridinecyclohexane-1,4-diamine compounds according to the invention, optionallyin the form of their racemates, their pure stereoisomers, in particularenantiomers or diastereomers, or in the form of mixtures ofstereoisomers, in particular enantiomers or diastereomers, in any mixingratio; in the form described or in the form of their acids or theirbases or in the form of their salts, in particular the physiologicallycompatible salts or salts of physiologically compatible acids orcations; or in the form of their solvates, in particular hydrates; forthe treatment of anxiety conditions, stress and stress-relatedsyndromes, depression, epilepsy, Alzheimer's disease, senile dementia,general cognitive disfunctions, learning and memory difficulties (as anootropic), withdrawal symptoms, alcohol and/or drug and/or medicationabuse and/or dependency, sexual dysfunctions, cardiovascular diseases,hypotension, hypertension, tinnitus, pruritus, migraines, hearingdifficulties, deficient intestinal motility, eating disorders, anorexia,obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinenceor for use as a muscle relaxant, anticonvulsive agent or anaesthetic orfor coadministration in treatment with an opioid analgesic or with ananaesthetic, for diuresis or antinatriuresis and/or anxiolysis.

[0136] In the above applications it can be advantageous if a substituted2-pyridine cyclohexane-1,4-diamine compound that is used is present as apure diastereomer and/or enantiomer, as a racemate or as a non-equimolaror equimolar mixture of diastereomers and/or enantiomers.

[0137] The present invention also provides a process for the treatment,in particular in one of the above indications, of a non-human mammal orhuman requiring treatment for pain, in particular chronic pain, byadministration of a therapeutically effective dose of a substituted2-pyridine cyclohexane-1,4-diamine compound according to the inventionor of a medicament according to the invention.

[0138] The invention also provides a process for the production of thesubstituted 2-pyridine cyclohexane-1,4-diamine compounds according tothe invention as set out in the description and the following examples.

[0139] Particularly suitable is a process for the production of asubstituted 2-pyridine cyclohexane-1,4-diamine compound according to theinvention corresponding to formula I where R³═H, referred to below asmain process A, comprising the following steps:

[0140] a. a cyclohexane-1,4-dione protected with groups S¹ and S²according to formula II is reacted in the presence of a compound havingthe formula HNR⁰¹R⁰² with a cyanide, preferably potassium cyanide, togive a protected N-substituted 1-amino-4-oxocyclohexane carbonitrilecompound according to formula III;

[0141] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H protected by a protectivegroup, a protective group is eliminated at least once and acylation,alkylation or sulfonation optionally performed and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H, a protective group isintroduced at least once and acylation, alkylation or sulfonationoptionally performed,

[0142] b. the aminonitrile according to formula III is brought intocontact with cyclopentadienyl cycloocta-1,5-diene cobalt (I) [cpCo(cod)]and irradiated under acetylene, such that a compound according toformula IVa is produced;

[0143] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H protected by a protectivegroup, a protective group is eliminated at least once and acylation,alkylation or sulfonation optionally performed and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H, a protective group isintroduced at least once and acylation, alkylation or sulfonationoptionally performed,

[0144] c. the protective groups S¹ and S² are eliminated at the compoundaccording to formula IVa such that a tetrasubstituted4-aminocyclohexanone compound according to formula IV is produced;

[0145] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H protected by a protectivegroup, a protective group is eliminated at least once and acylation,alkylation or sulfonation optionally performed and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H, a protective group isintroduced at least once and acylation, alkylation or sulfonationoptionally performed,

[0146] d. the tetrasubstituted 4-aminocyclohexanone compound accordingto formula IVa is reductively aminated with a compound having theformula HNR⁰⁴R⁰⁵ such that a 2-pyridine cyclohexane-1,4-diamine compoundaccording to formula V is produced;

[0147] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶=Hprotected by a protective group, a protective group is eliminated atleast once and acylation, alkylation or sulfonation optionally performedand/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/orR⁰⁵ and/or R⁰⁶=H, a protective group is introduced at least once andacylation, alkylation or sulfonation optionally performed, until acompound according to formula I is produced,

[0148] wherein R¹, R², R⁴ and R⁵ have the meaning given for thecompounds according to the invention according to formula I

[0149] and

[0150] R⁰¹ and R⁰² are independently selected from H; H provided with aprotective group; C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl or heteroaryl, each being mono- or polysubstitutedor unsubstituted; or aryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃alkylene, each being mono- or polysubstituted or unsubstituted;

[0151] or the radicals R⁰¹ and R⁰² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR⁰⁶CH₂CH₂ or (CH₂)₃₋₆,

[0152] where R⁰⁶ is selected from H; H provided with a protective group;C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; arylor heteroaryl, each being mono- or polysubstituted or unsubstituted; oraryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃ alkylene, each beingmono- or polysubstituted or unsubstituted;

[0153] R⁰⁴ is selected from H, H provided with a protective group; C₁₋₈alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0154] R⁰⁵ is selected from H, H provided with a protective group; C₃₋₈cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- orpolysubstituted; —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹²,—CHR¹′-CH₂—CH₂—CH₂R¹², —C(Y)R₁₁-1(Y)-CH₂R¹², —C(Y)—CH₂—CH₂R¹² or—C(Y)—CH₂—CH₂—CH₂R¹²

[0155] where Y═H₂,

[0156] where R¹¹ is selected from H, C₁₋₇ alkyl, saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted;

[0157] and where R¹² is selected from H; C₃₋₈ cycloalkyl, aryl orheteroaryl, each being unsubstituted or mono- or polysubstituted,

[0158] or R⁰⁴ and R⁰⁵ together form a heterocyclic compound with between3 and 8 atoms in the ring, saturated or unsaturated; mono- orpolysubstituted or unsubstituted,

[0159] and S¹ and S² are independently selected from protective groupsor together denote a protective group, preferably monoacetal.

[0160] Particularly suitable is a process for the production of asubstituted 2-pyridine cyclohexane-1,4-diamine compound according to theinvention according to formula I where R³═H, referred to below asalternative process A, comprising the following steps:

[0161] a. a cyclohexane-1,4-dione protected with groups Si and S²according to formula II is reductively aminated with a compound havingthe formula HNR⁰⁴R⁰⁵ such that a 4-aminocyclohexanone compound accordingto formula VI is produced;

[0162] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰⁴ and/or R⁰⁵=H protected by a protective group, aprotective group is eliminated at least once and acylation, alkylationor sulfonation optionally performed and/or in the case of compoundswhere R⁰⁴ and/or R⁰⁵=H, a protective group is introduced at least onceand acylation, alkylation or sulfonation optionally performed,

[0163] b. the 4-aminocyclohexanone compound according to formula VI isreacted in the presence of a compound having the formula HNR⁰¹R⁰² withcyanide, preferably potassium cyanide, to give a cyclohexanone nitrilecompound having formula VII,

[0164] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶=Hprotected by a protective group, a protective group is eliminated atleast once and acylation, alkylation or sulfonation optionally performedand/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/orR⁵ and/or R⁰⁶=H, a protective group is introduced at least once andacylation, alkylation or sulfonation optionally performed,

[0165] c. the cyclohexanone nitrile compound having formula VII isbrought into contact with cyclopentadienyl cycloocta-1,5-diene cobalt(I) [cpCo(cod)] and irradiated under acetylene, such that a 2-pyridinecyclohexane-1,4-diamine compound according to formula V is produced,

[0166] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶=Hprotected by a protective group, a protective group is eliminated atleast once and acylation, alkylation or sulfonation optionally performedand/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/orR⁰⁵ and/or R⁰⁶=H, a protective group is introduced at least once andacylation, alkylation or sulfonation optionally performed, until acompound according to formula I is produced,

[0167] wherein R¹, R², R⁴ and R⁵ have the meaning given for thecompounds according to the invention according to formula I

[0168] and

[0169] R⁰¹ and R⁰² are independently selected from H; H provided with aprotective group; C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl or heteroaryl, each being mono- or polysubstitutedor unsubstituted; or aryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃alkylene, each being mono- or polysubstituted or unsubstituted;

[0170] or the radicals R⁰¹ and R⁰² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR⁰⁶CH₂CH₂ or (CH₂)₃₋₆,

[0171] where R⁰⁶ is selected from H; H provided with a protective group;C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; arylor heteroaryl, each being mono- or polysubstituted or unsubstituted; oraryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃ alkylene, each beingmono- or polysubstituted or unsubstituted;

[0172] R⁰⁴ is selected from H, H provided with a protective group; C₁₋₈alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0173] R⁰⁵ is selected from H provided with a protective group; C₃₋₈cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- orpolysubstituted; —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹²,—CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹² or—C(Y)—CH₂—CH₂—CH₂R¹²

[0174] where Y═H₂,

[0175] where R¹¹ is selected from

[0176] H, C₁₋₇ alkyl, saturated or unsaturated, branched or unbranched,mono- or polysubstituted or unsubstituted;

[0177] and where R¹² is selected from H; C₃₋₈ cycloalkyl, aryl orheteroaryl, each being unsubstituted or mono- or polysubstituted,

[0178] or R⁰⁴ and R⁰⁵ together form a heterocyclic compound with between3 and 8 atoms in the ring, saturated or unsaturated; mono- orpolysubstituted or unsubstituted,

[0179] and S¹ and S2 are independently selected from protective groupsor together denote a protective group, preferably monoacetal.

[0180] For both processes A it is particularly advantageous if theprotective groups at H in R⁰¹, R⁰², R⁰⁴, R⁰⁵ and/or R⁰⁶ are selectedfrom alkyl, benzyl or carbamates, for example FMOC, Z or Boc.

[0181] For the main process A it is particularly advantageous if thereductive amination in step d takes place in the presence of ammoniumformate, ammonium acetate or NaCNBH₃.

[0182] For the main process A it is particularly advantageous if insteadof the reductive amination with HNR⁰⁴R⁰⁵ in step d, compound IV isreacted with hydroxylamine and reduced after oxime formation.

[0183] For the main process A it is particularly advantageous if theirradiation in step b lasts between 5 and 7 h and/or takes place at roomtemperature and/or in a saturated acetylene atmosphere and/or underprotective gas.

[0184] For the alternative process A it is particularly advantageous ifthe irradiation in step c lasts between 5 and 7 h and/or takes place atroom temperature and/or in a saturated acetylene atmosphere and/or underprotective gas.

[0185] Also suitable is a process for the production of a substituted2-pyridine cyclohexane-1,4-diamine compound according to the invention,referred to below as main process B, comprising the following steps:

[0186] a. a cyclohexane-1,4-dione protected with groups S¹ and S²according to formula II is reacted in the presence of a compound havingthe formula HNR⁰¹R⁰² with a cyanide, preferably potassium cyanide, togive a protected N-substituted 1-amino-4-oxocyclohexane carbonitrilecompound according to formula III;

[0187] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H protected by a protectivegroup, a protective group is eliminated at least once and acylation,alkylation or sulfonation optionally performed and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H, a protective group isintroduced at least once and acylation, alkylation or sulfonationoptionally performed,

[0188] b. the aminonitrile according to formula III is reacted withorganometallic reagents, preferably Grignard or organolithium reagents,having the formula metal-2-pyridine-R³, such that a compound accordingto formula IVa is produced;

[0189] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H protected by a protectivegroup, a protective group is eliminated at least once and acylation,alkylation or sulfonation optionally performed and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H, a protective group isintroduced at least once and acylation, alkylation or sulfonationoptionally performed,

[0190] c. the protective groups S¹ and S² are eliminated at the compoundaccording to formula IVa such that a tetrasubstituted4-aminocyclohexanone compound according to formula IV is produced;

[0191] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H protected by a protectivegroup, a protective group is eliminated at least once and acylation,alkylation or sulfonation optionally performed and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁶=H, a protective group isintroduced at least once and acylation, alkylation or sulfonationoptionally performed,

[0192] d. the tetrasubstituted 4-aminocyclohexanone compound accordingto formula IVa is reductively aminated with a compound having theformula HNR⁰⁴R⁰⁵ such that a 2-pyridine cyclohexane-1,4-diamine compoundaccording to formula V is produced;

[0193] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶=Hprotected by a protective group, a protective group is eliminated atleast once and acylation, alkylation or sulfonation optionally performedand/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/orR⁰⁵ and/or R⁰⁶=H, a protective group is introduced at least once andacylation, alkylation or sulfonation optionally performed, until acompound according to formula I is produced,

[0194] wherein R¹, R², R⁴ and R⁵ have the meaning given for thecompounds according to the invention according to formula I

[0195] and

[0196] R⁰¹ and R⁰² are independently selected from H; H provided with aprotective group; C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl or heteroaryl, each being mono- or polysubstitutedor unsubstituted; or aryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃alkylene, each being mono- or polysubstituted or unsubstituted;

[0197] or the radicals R⁰¹ and R⁰² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR⁰⁶CH₂CH₂ or (CH₂)₃₋₆,

[0198] where R⁰⁶ is selected from H; H provided with a protective group;C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; arylor heteroaryl, each being mono- or polysubstituted or unsubstituted; oraryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃ alkylene, each beingmono- or polysubstituted or unsubstituted;

[0199] R⁰⁴ is selected from H, H provided with a protective group; C₁₋₈alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0200] R⁰⁵ is selected from H, H provided with a protective group; C₃₋₈cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- orpolysubstituted; —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹²,—CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹² or—C(Y)—CH₂—CH₂—CH₂R¹²

[0201] where Y═H₂,

[0202] where R¹¹ is selected from

[0203] H, C₁₋₇ alkyl, saturated or unsaturated, branched or unbranched,mono- or polysubstituted or unsubstituted;

[0204] and where R¹² is selected from H; C₃₋₈ cycloalkyl, aryl orheteroaryl, each being unsubstituted or mono- or polysubstituted,

[0205] or R⁰⁴ and R⁰⁵ together form a heterocyclic compound with between3 and 8 atoms in the ring, saturated or unsaturated; mono- orpolysubstituted or unsubstituted,

[0206] and S¹ and S² are independently selected from protective groupsor together denote a protective group, preferably monoacetal.

[0207] The term alkylation here also includes a reductive amination,since it leads to the same result.

[0208] The invention also preferably provides a process for theproduction of a substituted 2-pyridine cyclohexane-1,4-diamine compoundaccording to the invention, referred to below as alternative process B,comprising the following steps:

[0209] a. a cyclohexane-1,4-dione protected with groups S¹ and S²according to formula II is reductively aminated with a compound havingthe formula HNR⁰⁴R⁰⁵ such that a 4-aminocyclohexanone compound accordingto formula VI is produced;

[0210] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰⁴ and/or R⁰⁵=H protected by a protective group, aprotective group is eliminated at least once and acylation, alkylationor sulfonation optionally performed and/or in the case of compoundswhere R⁰⁴ and/or R⁰⁵=H, a protective group is introduced at least onceand acylation, alkylation or sulfonation optionally performed,

[0211] b. the 4-aminocyclohexanone compound according to formula VI isreacted in the presence of a compound having the formula HNR⁰¹R⁰² withcyanide, preferably potassium cyanide, to give a cyclohexanone nitrilecompound having formula VII,

[0212] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶=Hprotected by a protective group, a protective group is eliminated atleast once and acylation, alkylation or sulfonation optionally performedand/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/orR⁰⁵ and/or R⁰⁶=H, a protective group is introduced at least once andacylation, alkylation or sulfonation optionally performed,

[0213] c. the cyclohexanone nitrile compound having formula VII isreacted with organometallic reagents, preferably Grignard ororganolithium reagents, having the formula metal-2-pyridine-R³ and theprotective groups S¹ and S² finally eliminated such that a 2-pyridinecyclohexane-1,4-diamine compound according to formula V is produced,

[0214] acylation, alkylation or sulfonation is then optionally performedin any sequence and optionally more than once and/or in the case ofcompounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶=Hprotected by a protective group, a protective group is eliminated atleast once and acylation, alkylation or sulfonation optionally performedand/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/orR⁰⁵ and/or R⁰⁶=H, a protective group is introduced at least once andacylation, alkylation or sulfonation optionally performed, until acompound according to formula I is produced,

[0215] wherein R¹, R², R⁴ and R⁵ have the meaning given for thecompounds according to the invention according to formula I

[0216] and

[0217] R⁰¹ and R⁰² are independently selected from H; H provided with aprotective group; C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl or heteroaryl, each being mono- or polysubstitutedor unsubstituted; or aryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃alkylene, each being mono- or polysubstituted or unsubstituted;

[0218] or the radicals R⁰¹ and R⁰² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR⁰⁶CH₂CH₂ or (CH₂)₃₋₆,

[0219] where R⁰⁶ is selected from H; H provided with a protective group;C₁₋₈ alkyl or C₃₋₈ cycloalkyl, each being saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; arylor heteroaryl, each being mono- or polysubstituted or unsubstituted; oraryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃ alkylene, each beingmono- or polysubstituted or unsubstituted;

[0220] R⁰⁴ is selected from H, H provided with a protective group; C₁₋₈alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted;

[0221] R⁰⁵ is selected from H provided with a protective group; C₃₋₈cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- orpolysubstituted; —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹²,—CHR¹¹—CH₂—CH₂—CH₂R¹², —(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹² or—C(Y)—CH₂—CH₂—CH₂R¹²

[0222] where Y═H₂,

[0223] where R¹¹ is selected from H, C₁₋₇ alkyl, saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted;

[0224] and where R¹² is selected from

[0225] H; C₃₋₈ cycloalkyl, aryl or heteroaryl, each being unsubstitutedor mono- or polysubstituted,

[0226] or R⁰⁴ and R⁰⁵ together form a heterocyclic compound with between3 and 8 atoms in the ring, saturated or unsaturated; mono- orpolysubstituted or unsubstituted,

[0227] and S¹ and S² are independently selected from protective groupsor together denote a protective group, preferably monoacetal.

[0228] For both processes B it is further preferable that the protectivegroups at H in R⁰¹, R¹², R⁰⁴, R⁰⁵ and/or R⁰⁶ are selected from alkyl,benzyl or carbamates, for example FMOC, Z or Boc.

[0229] For the main process B it is preferable if the reductiveamination in step d takes place in the presence of ammonium formate,ammonium acetate or NaCNBH₃.

[0230] For the main process B it is also a particularly advantageousembodiment if instead of the reductive amination with HNR⁰⁴R⁰⁵ in stepd, compound IV is reacted with hydroxylamine and reduced after oximeformation.

[0231] It is equally advantageous for the alternative process B if instep b the radical R⁰¹ in formula HNR⁰¹R⁰² is H, the reaction withcyanide occurs with TMSCN and a protective group is then optionallyintroduced at R⁰¹.

[0232] The invention will be described in further detail below withreference to illustrative working examples, without being restricted tothem.

EXAMPLES

[0233] The following examples are intended to illustrate the inventionin more detail but do not restrict the general concepts of theinvention.

[0234] The yields of the compounds produced are not optimized. Alltemperatures are uncorrected.

[0235] The reference “ether” denotes diethyl ether, “EE” denotes ethylacetate and “DCM” dichloromethane. The reference “equivalents” denotessubstance amount equivalents, “mp” denotes melting point or meltingrange, “RT” denotes room temperature, “vol. %” percent by volume, “m %”percent by mass and “M” is a measure of concentration in mole/liter.

[0236] Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, was usedas the stationary phase for column chromatography. Examinations bythin-layer chromatography were performed with HPTLC chromatoplates,silica gel 60° F. 254, from E. Merck, Darmstadt. The mixing ratios formobile solvents for chromatographic examinations are always given involume/volume.

Example 1 N′-benzyl-N,N-dimethyl-1-phenyl cyclohexane-1,4-diaminehydrochloride, non-polar diastereomer Example 1N-(4-dimethylamino-4-pyridin-2-yl cyclohexyl)-N-[2-(1H-indol-3-yl)ethyl]acetamide dihydrochloride, non-polar diastereomer

[0237] 200 ml methanol, 1680 ml aqueous dimethylamine solution (40 m %),303 g dimethylamine hydrochloride and 200 g potassium cyanide were addedto 200 g 1,4-dioxaspiro[4.5]decan-8-one and stirred for approximately 65hours. The resulting white suspension was extracted four times with 800ml ether each time, the combined extracts concentrated to low volume,the residue taken up in approximately 500 ml dichloromethane and thephases separated. The organic phase was dried over sodium sulfate,filtered and concentrated to low volume. 265 g8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were obtainedas a white solid.

[0238] A solution of 4.5 g8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile, 50 mgcyclopentadienyl cycloocta-1,5-diene cobalt (I) [cpCo(cod)] and 100 mltoluene were transferred into the reaction vessel in a protectivegas/acetylene counterflow. After saturation with acetylene the reactionsolution was irradiated for a period of 6 hours at a temperature of 25°C. with vigorous stirring. The reaction was interrupted by switching offthe lamps and air supply, and the reaction solution was concentrated tolow volume. The resulting crude product (5.47 g) was taken up in amixture of water (8.7 ml) and concentrated hydrochloric acid (15 ml) andstirred overnight at room temperature. To recover the product it waswashed with diethyl ether (3×100 ml), the phases separated, the aqueousphase alkalified with 32 percent by mass of sodium hydroxide solution,extracted with dichloromethane (3×100 ml), the combined extracts dried(Na₂SO₄), filtered and concentrated to low volume. 3.72 g4-dimethylamino-4-pyridin-2-yl cyclohexanone were obtained.

[0239] Acetic acid (0.448 ml) was added to a solution of4-dimethylamino-4-pyridin-2-yl cyclohexanone (873 mg) and tryptamine(640 mg) in dry tetrahydrofuran (40 ml) and anhydrous 1,2-dichloroethane(10 ml) and stirred for 15 min. Following addition of sodiumtriacetoxyboron hydride (1.2 g) the reaction mixture was stirred forthree days under argon at room temperature. To recover the product thesolvent was removed in vacuo, the residue taken up in 1N sodiumhydroxide solution (40 ml) and diethyl ether (40 ml), the phasesseparated, the aqueous phase extracted with diethyl ether (2×30 ml), theorganic phases combined, dried and concentrated to low volume. Theresulting raw product was separated by column chromatography on silicagel with methanol and methanol/ammonia (100:1). The non-polardiastereoisomer ofN′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine was obtained as a white solid (617 mg; mp150-152° C.).

[0240] N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine (250 mg) was dissolved in dry pyridine (5 ml),acetic anhydride (0.64 ml) was added and the mixture was stirred for 22hours at room temperature. Some ice was added to the reaction mixtureand it was then concentrated to low volume. The residue was taken up in1M sodium hydroxide solution (20 ml) and ethyl acetate (20 ml) andstirred. A white solid was left behind, which could be suction filtered(86 mg). The aqueous phase of the filtrate was extracted with ethylacetate (2×20 ml). The combined organic extracts were concentrated tolow volume after drying. The residue obtained in this way was identicalto the solid obtained earlier. Both substances were combined. 219 mgN-(4-dimethylamino-4-pyridin-2-yl cyclohexyl)-N-[2-(1H-indol-3-yl)ethyl]acetamide were obtained (mp 209-210° C.), of which 195 mg were dissolvedin 2-butanone (25 ml) with gentle heating to 40° C. and converted intothe corresponding dihydrochloride with chlorotrimethyl silane (0.303 ml)(white solid; 219 mg; mp 244-247° C.).

Example 2 N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride, non-polar diastereomer

[0241] The N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine obtained according to example 1 (342 mg) wasdissolved in 2-butanone (20 ml) and converted to the correspondingtrihydrochloride with chlorotrimethyl silane (0.59 ml) (beige-colouredsolid; 408 mg).

Example 3 N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride, polar diastereoisomer

[0242] As described for example 1, 171 mg of the polar diastereoisomerof N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine were also obtained, dissolved in 2-butanone (20ml) and converted into the corresponding trihydrochloride withchlorotrimethyl silane (0.297 ml) (171 mg beige solid, mp 225-230° C.).

Example 4 N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride, non-polar diastereoisomer

[0243] The hydrochloride of L-tryptophane methyl ester (1.01 g) wasstirred vigorously with 1,2-dichloroethane (20 ml) and saturated NaHCO₃solution (20 ml) for 15 min, and the aqueous phase was extracted with1,2-dichloroethane (2×20 ml). After drying with Na₂SO₄ the organic phasewas concentrated to 40 ml, and 4-dimethylamino-4-pyridin-2-ylcyclohexanone (873 mg) was added under argon. Glacial acetic acid (0.448ml) and Na₂SO₄ (2 g) were added to the clear solution. After a reactiontime of 15 min NaBH(OAc)₃ (1.2 g) was added to the reaction mixture, andit was stirred for four days at room temperature. To recover the productsaturated NaHCO₃ solution (40 ml) was added to the mixture, and it wasstirred for 15 min. The aqueous phase was extracted with dichloromethane(2×30 ml), and the combined organic phases were concentrated to lowvolume after drying to obtain a light-brown oil. Chromatographicseparation of the mixture of substances on silica gel was performed withethyl acetate/methanol (4:1) and methanol. The non-polar product (820 mglight oily compound) was dissolved in 2-butanone (50 ml) and convertedto the trihydrochloride with chlorotrimethyl silane (1.22 ml) (719 mgwhite hygroscopic solid; [α]_(D) ²⁰=19.85 (MeOH, c=1.33)).

Example 5 (S)-2-(4-dimethylamino-4-pyridin-2-ylcyclohexylamino)-3-(1H-indol-3-yl) methyl propionate trihydrochloride,polar diastereomer

[0244] As described in example 4, 284 mg of the polar diastereoisomer of(S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl)methyl propionate were also obtained, dissolved in 2-butanone (15 ml)and converted to the corresponding trihydrochloride with chlorotrimethylsilane (0.43 ml) (171 mg white solid; mp 170-175° C.; [α]_(D) ²⁰=17.61(MeOH, c=1.45)).

Example 6 (S)-2-(4-dimethylamino-4-pyridin-2-ylcyclohexylamino)-3-(1H-indol-3-yl) propionic acid dihydrochloride,non-polar diastereomer

[0245] 1.7N KOH (8.8 ml) was added to a solution of the non-polardiastereoisomer ofN′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride produced according to example 4(378 mg) in ethanol (20 ml). After 70 hours it was concentrated to lowvolume, the remaining yellow oil dissolved in water (10 ml), the aqueousphase washed with ethyl acetate (3×20 ml) and 5.5N HCl (9.0 ml) added.The aqueous phase was concentrated to low volume and the residuedigested with ethanol (2×20 ml). The remaining KCl was separated out andthe filtrate concentrated to low volume and washed with ether. Thedihydrochloride of (S)-2-(4-dimethylamino-4-pyridin-2-ylcyclohexylamino)-3-(1H-indol-3-yl) propionic acid dihydrochloride,non-polar, was obtained in this process (307 mg [α]_(D) ²⁰=20.69 (MeOH,c=1.213)).

Example 8 Measurement of ORL1 Binding

[0246] The cyclohexane-1,4-diamine compounds corresponding to theformula I were investigated in a receptor binding assay with³H-nociceptin/orphanin FQ with membranes of recombinant CHO—ORL1 cells.This test system was performed according to the method put forward byArdati et al. (Mol., Pharmacol., 51, 1997, p. 816-824). Theconcentration of ³H-in/orphanin nociceptin/orphanin FQ in these testswas 0.5 nM. The binding assays were performed with 20 μg membraneprotein per 200 μl batch in 50 mM hepes, pH 7.4, 10 mM MgCl₂ and 1 mMEDTA. Binding to the ORL1 receptor was determined using 1 mg WGA-SPAbeads (Amersham-Pharmacia, Freiburg) by incubation of the batch for onehour at room temperature followed by measurement in a Triluxscintillation counter (Wallac, Finland). The affinity is given as theK_(i) value in μM. ORL1 Example Ki/μM 1 0.18 2 0.013 3 0.34 4 0.093 50.47 6 0.28

Example 9 Analgesia Testing in the Tail Flick Test in Mice

[0247] The mice were placed individually into a test cage and the baseof the tail exposed to a focused beam of heat from an electric lamp(tail flick type 50/08/1.bc, Labtec, Dr. Hess). The lamp intensity wasadjusted so that the time from switching on the lamp to the suddenflicking away of the tail (pain latency) for untreated mice was 3 to 5seconds. Before administration of the solutions containing the compoundaccording to the invention or the comparative solutions the mice werepre-tested twice within five minutes and the mean of these measurementscalculated as the pre-test mean.

[0248] The solutions of the compound according to the inventioncorresponding to the formula I and the comparative solutions were thenadministered intravenously. The pain was measured at 10, 20, 40 and 60minutes after intravenous administration. The analgesic activity wasdetermined as the increase in pain latency (% of the maximum possibleantinociceptive effect) according to the formula below:

% MPE=[(T ₁ −T ₀)/(T ₂ −T _(O))]×100

[0249] In this formula the time T₀ is the latency time beforeadministration, the time T₁ the latency time after administration of theactive ingredient combination and the time T₂ the maximum exposure time(12 seconds)

[0250] The compounds according to the invention that were examineddisplayed an analgesic effect. The results of selected tests aresummarized in the following table. TABLE % MPE in comparison to Exampleno. control group 1 71 (10) 4 91 (10)

[0251] The dose in mg/kg for intravenous administration is given inparentheses.

Example 10 Parenteral solution of a substituted 2-pyridinecyclohexane-1,4-diamine compound according to the invention

[0252] 38 g of the substituted 2-pyridine cyclohexane-1,4-diaminecompounds according to the invention, in this case according to example1, is dissolved in 1 liter of sterile, injectable water at roomtemperature and then adjusted to isotonic conditions by addition ofanhydrous injectable glucose.

[0253] The foregoing description and examples have been set forth merelyto illustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

What is claimed is:
 1. A substituted 2-pyridine cyclohexane-1,4-diaminecompound corresponding to formula I

wherein R¹ and R² are independently selected from the group consistingof H; C₁₋₈ alkyl and C₃₋₈ cycloalkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl and heteroaryl, each being mono- or polysubstitutedor unsubstituted; and aryl, C₃₋₈ cycloalkyl or heteroaryl bonded viaC₁₋₃ alkylene, each being mono- or polysubstituted or unsubstituted; orR¹ and R² together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂or (CH₂)₃₋₆, where R⁶ is selected from the group consisting of H; C₁₋₈alkyl and C₃₋₈ cycloalkyl, each being saturated or unsaturated, branchedor unbranched, mono- or polysubstituted or unsubstituted; aryl andheteroaryl, each being mono- or polysubstituted or unsubstituted; andaryl, C₃₋₈ cycloalkyl and heteroaryl bonded via C₁₋₃ alkylene, eachbeing mono- or polysubstituted or unsubstituted; R³ is selected from thegroup consisting of H; C₁₋₈ alkyl, saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted; C₃₋₈ cycloalkyl,saturated or unsaturated, mono- or polysubstituted or unsubstituted;aryl and heteroaryl, each being mono- or polysubstituted orunsubstituted; aryl, C₃₋₈ cycloalkyl and heteroaryl each bonded via C₁₋₃alkylene and each being mono- or polysubstituted or unsubstituted; SH,OH, F, Cl, I, Br, CN, NO₂, OR²⁶, and NR²⁷R²⁸; where R²⁶ is selected fromthe group consisting of C₁₋₆ alkyl, saturated or unsaturated, branchedor unbranched, mono- or polysubstituted or unsubstituted; C₃₋₈cycloalkyl, saturated or unsaturated, mono- or polysubstituted orunsubstituted; aryl and heteroaryl, each being unsubstituted or mono- orpolysubstituted with at least one substituent selected from the groupconsisting of F, Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂Hs, C₃H₇,C₄H₉, OCF₃, OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and OH; aryl,C₃₋₈ cycloalkyl and heteroaryl each bonded via C₁₋₃ alkyl, saturated orunsaturated, and each being unsubstituted or mono- or polysubstitutedwith at least one substituent selected from the group consisting of F,Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃,OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and OH; R²⁷ and R²⁸ areindependently selected from the group consisting of H; C₁₋₆ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; C₃₋₈ cycloalkyl, saturated orunsaturated, mono- or polysubstituted or unsubstituted; aryl andheteroaryl, each being unsubstituted or mono- or polysubstituted with atleast one substituent selected from the group consisting of F, Cl, Br,I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃, OCHF₂, OCH₂F,OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and OH; aryl, C₃₋₈ cycloalkyl andheteroaryl each bonded via C₁₋₃ alkyl, saturated or unsaturated, andeach being unsubstituted or mono- or polysubstituted with at least onesubstituent selected from the group consisting of F, Cl, Br, I, NH₂,NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃, OCHF₂, OCH₂F, OCH₃,OC₂H₅, OC₃H₇, OC₄H₉, SH and OH; or R²⁷ and R²⁸ together denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR²CH₂CH₂ or (CH₂)₃₋₆, where R²⁹ is selected fromthe group consisting of H; C₁₋₆ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; C₃₋₈cycloalkyl, saturated or unsaturated, mono- or polysubstituted orunsubstituted; aryl and heteroaryl, each being unsubstituted or mono- orpolysubstituted with at least one substituent selected from the groupconsisting of F, Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇,C₄H₉, OCF₃, OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and OH; aryl,C₃₋₈ cycloalkyl and heteroaryl each bonded via C₁₋₃ alkyl, saturated orunsaturated, and each being unsubstituted or mono- or polysubstitutedwith at least one substituent selected from the group consisting of F,Cl, Br, I, NH₂, NO₂, CF₃, CHF₂, CH₂F, CH₃, C₂H₅, C₃H₇, C₄H₉, OCF₃,OCHF₂, OCH₂F, OCH₃, OC₂H₅, OC₃H₇, OC₄H₉, SH and OH; R⁴ is selected fromthe group consisting of H; C₁₋₈ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted;C(X)R⁷; C(X)NR⁷R⁸; C(X)OR⁹; C(X)SR⁹; and S(O₂)R⁹, where X═O or S, R⁷ isselected from the group consisting of H; C₁₋₈ alkyl and C₃₋₈ cycloalkyl,each being saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; aryl and heteroaryl, each beingunsubstituted or mono- or polysubstituted; aryl, C₃₋₈ cycloalkyl andheteroaryl, each bonded via a saturated or unsaturated, branched orunbranched, substituted or unsubstituted C₁₋₄ alkyl group, and eachbeing unsubstituted or mono- or polysubstituted; R⁸ is H or C₁₋₄ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted, or R⁷ and R⁸ together form a ring anddenote CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹CH₂CH₂ or (CH₂)₃₋₆, where R¹⁰ is selectedfrom the group consisting of H; C₁₋₈ alkyl and C₃₋₈ cycloalkyl, eachbeing saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; aryl and heteroaryl, each being mono-or polysubstituted or unsubstituted; and aryl, C₃₋₈ cycloalkyl andheteroaryl, each bonded via C₁₋₃ alkylene, and each being mono- orpolysubstituted or unsubstituted; and R⁹ is selected from the groupconsisting of C₁₋₈ alkyl, C₃₋₈ cycloalkyl, each being saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl, heteroaryl, each being unsubstituted or mono- orpolysubstituted; and aryl, C₃₋₈ cycloalkyl or heteroaryl bonded via asaturated or unsaturated, branched or unbranched, substituted orunsubstituted C₁₋₄ alkyl group, each being unsubstituted or mono- orpolysubstituted; R⁵ is selected from the group consisting of C₃₋₈cycloalkyl, aryl, heteroaryl., each being unsubstituted or mono- orpolysubstituted; —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹²,—CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂-CH₂R¹² and—C(Y)—CH₂—CH₂—CH₂R¹², where Y═O, S or H₂, where R¹¹ is selected from thegroup consisting of H; C₁₋₇ alkyl, saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted; and C(O)O—C₁₋₁₆alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; and R¹² is selected from the groupconsisting of H, C₃₋₈ cycloalkyl, aryl and heteroaryl, wherein the C₃₋₈cycloalkyl, aryl and heteroaryl may be unsubstituted or mono- orpolysubstituted, or R⁴ and R⁵ together form a heterocyclic ringcontaining from 3 to 8 atoms, saturated or unsaturated, mono- orpolysubstituted or unsubstituted, which can optionally be condensed withother rings, wherein said compound is in the form of a racemate, a purestereoisomer, a mixture of stereoisomers in any mixing ratio, a freebase, a salt or a solvate.
 2. A compound according to claim 1, whereinR¹ and R² are independently selected from the group consisting of H andC₁₋₈ alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; or R¹ and R² together form a ring anddenote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂ or (CH₂)₃₋₆, where R⁶ is selectedfrom the group consisting of H and C₁₋₈ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted.
 3. Acompound according to claim 2, wherein R¹ and R² are independentlyselected from the group consisting of H and C₁₋₄ alkyl, saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted, or R¹ and R² together form a ring and denote (CH₂)₄₋₅. 4.A compound according to claim 3, wherein R¹ and R² are independentlyselected from methyl and ethyl, or R¹ and R² together form a ring anddenote (CH₂)₅.
 5. A compound according to claim 1, wherein R³ isselected from the group consisting of H; C₁₋₈ alkyl, each beingsaturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; C₃₋₈ cycloalkyl, saturated orunsaturated, mono-or polysubstituted or unsubstituted; aryl orheteroaryl, each being mono- or polysubstituted or unsubstituted; oraryl, C₃₋₈ cycloalkyl or heteroaryl bonded via C₁₋₃ alkylene, each beingmono- or polysubstituted or unsubstituted; SH, OH, F, Cl, I, Br, CN,NO₂, NH₂, and OR², where R²⁶ is C₁₋₆ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted.
 6. Acompound according to claim 1, wherein R³ is selected from the groupconsisting of H; C₁₋₆ alkyl, each being saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted; SH,OH, F, Cl, I, Br, CN, NO₂, NH₂, and OR²⁶, where R²⁶ is selected fromC₁₋₆ alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted.
 7. A compound according to claim 6,wherein R³ is H.
 8. A compound according to claim 1, wherein R⁴ isselected from the group consisting of H, C(X)R⁷, C(X) NR⁷R⁸, C(X)OR⁹,C(X)SR⁹ and S(O₂)R⁹, where X═O or S.
 9. A compound according to claim 8,wherein R⁴ is selected from the group consisting of H, C(X)R⁷, C(X)NR⁷R⁸and C(X)OR⁹, where X=O.
 10. A compound according to claim 9, wherein R⁴is H or C(O)R⁷, where R⁷ is H or C₁₋₈ alkyl, saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted.
 11. Acompound according to claim 10, where R⁷ is H or C₁₋₃ alkyl, saturated,unsubstituted, branched or unbranched.
 12. A compound according to claim12, wherein R⁷ is CH₃.
 13. A compound according to claim 1, wherein R⁴and R⁵ together form an N-containing heterocyclic ring containing from 3to 8 atoms, saturated or unsaturated; mono- or polysubstituted orunsubstituted.
 14. A compound according to claim 13, wherein saidN-containing heterocyclic ring contains from 5 to 7 atoms, including inaddition to said N, zero or 1 other heteroatom selected from the groupconsisting of N, S and O.
 15. A compound according to claim 13, whereinthe heterocyclic ring formed by R⁴ and R⁵ together is condensed with atleast one other ring.
 16. A compound according to claim 15, wherein saidat least one other ring comprises an aromatic or heteroaromatic ring.17. A compound according to claim 16, wherein the aromatic orheteroaromatic ring is condensed at least one further aromatic orheteroaromatic ring.
 18. A compound according to claim 15, wherein theheterocyclic ring formed by R⁴ and R⁵ together is condensed with one ortwo other rings.
 19. A compound according to claim 15, wherein theheterocyclic ring formed by R⁴ and R⁵ together is condensed with twoother rings such that R⁴ and R⁵ together denote


20. A compound according to claim 1, wherein R⁴ is H or C₁₋₈ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted.
 21. A compound according to claim 20,wherein R⁴ is H or C₁₋₆ alkyl, saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted.
 22. A compoundaccording to claim 21, wherein R⁴ is H or saturated, unbranched andunsubstituted C₁₋₃ alkyl.
 23. A compound according to claims 1, whereinR⁵ is selected from the group consisting of C₃₋₈ cycloalkyl, aryl andheteroaryl, each being unsubstituted or mono- or polysubstituted.
 24. Acompound according to claim 23, wherein R⁵ is selected from the groupconsisting of cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl,benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl,carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl,pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl,benzo[1,2,5]thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl,benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl,pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, and quinazolinyl,each being unsubstituted or mono- or polysubstituted.
 25. A compoundaccording to claim 24, wherein RS is selected from the group consistingof cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl,indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl,benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl,thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl, eachbeing unsubstituted or mono- or polysubstituted.
 26. A compoundaccording to claim 1, wherein R⁵ is selected from the group consistingof —CHR¹¹R¹², —CHR¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹²,—C(Y)R¹, C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹², and —C(Y)—CH₂—CH₂—CH₂R¹², whereY═O, S or H₂.
 27. A compound according to claim 26, wherein R⁵ isselected from the group consisting of —CHR¹¹R¹², —CHR¹¹—CH₂R¹²,—CHR¹¹—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², and —C(Y)—CH₂—CH₂R¹², whereY═O or S.
 28. A compound according to claim 27, wherein R⁵ is selectedfrom the group consisting of —CHR¹¹R¹², —CHR¹¹—CH₂R¹²,—CHR¹¹—CH₂—CH₂R¹², —C(Y)R¹², and —C(Y)—CH₂R¹², where Y═O.
 29. A compoundaccording to claim 26, wherein R¹¹ is selected from the group consistingof H; C₁₋₄ alkyl, saturated or unsaturated, branched or unbranched,mono- or polysubstituted or unsubstituted; and C(O)O—C₁₋₄ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted.
 30. A compound according to claim 29,wherein R¹¹ is selected from the group consisting of H; C₁₋₄ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; and C(O)O—C₁₋₂ alkyl, saturated,unbranched, mono- or polysubstituted or unsubstituted.
 31. A compoundaccording to claim 30, wherein R¹¹ is selected from the group consistingof H, CH₃, C₂H₅, and C(O)O—CH₃.
 32. A compound according to claim 26,wherein R¹² is selected from the group consisting of C₃₋₈ cycloalkyl,aryl and heteroaryl, each being unsubstituted or mono- orpolysubstituted.
 33. A compound according to claim 32, wherein R¹² isselected from the group consisting of cyclobutyl, cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl,naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl,benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl,pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl,benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl,1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl,pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl,quinolinyl, isoquinolinyl, phthalazinyl, and quinazolinyl, each beingunsubstituted or mono- or polysubstituted.
 34. A compound according toclaim 33, wherein R¹² is selected from the group consisting ofcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl,naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl,benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl,pyridyl, pyrrolyl, pyrazinyl, and pyrimidyl, each being unsubstituted ormono- or polysubstituted.
 35. A compound according to claim 1, selectedfrom the group consisting of: N-(4-dimethylamino-4-pyridin-2-ylcyclohexyl)-N-[2-(1H-indol-3-yl)ethyl] acetamide dihydrochloride,non-polar diastereoisomer;N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride, non-polar diastereoisomer;N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-ylcyclohexane-1,4-diamine trihydrochloride, polar diastereoisomer;(S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl)methyl propionate trihydrochloride, non-polar diastereoisomer;(S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl)methyl propionate trihydrochloride, polar diastereoisomer; and(S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl)propionic acid dihydrochloride, non-polar diastereoisomer in the form ofa racemate, a pure stereoisomer, a mixture of stereoisomers in anydesired mixing ratio, a free base, a salt or a solvate.
 36. A compoundaccording to claim 1, wherein said compound is in the form of a pureenantiomer or diastereoisomer.
 37. A compound according to claim 1,wherein said compound is in the form of a mixture of enantiomers ordiastereoisomers.
 38. A compound according to claim 1, wherein saidcompound is in the form of a salt with a physiologically compatibleacid.
 39. A compound according to claim 1, wherein said compound is inthe form of a hydrate.
 40. A pharmaceutical composition comprising atleast one compound according to claim 1 and at least one carrier,adjuvant or another active substance.
 41. A pharmaceutical compositionaccording to claim 40, comprising said compound and an opioid or ananaesthetic.
 42. A pharmaceutical composition according to claim 41,comprising said compound and morphine or an anaesthetic selected fromthe group consisting of hexobarbital and halothane.
 43. A method oftreating pain in a patient, said method comprising administering to saidpatient an effective pain treating amount of at least one compoundaccording to claim
 1. 44. A method according to claim 43, wherein saidpain is acute pain, neuropathic pain, or chronic pain.
 45. A method oftreating a patient for a condition selected from the group consisting ofanxiety, stress, stress-related syndromes, depression, epilepsy,Alzheimer's disease, senile dementia, general cognitive disfunctions,learning and memory difficulties, withdrawal symptoms, alcoholdependency or abuse, drug dependency or abuse, medication dependency orabuse, sexual dysfunctions, cardiovascular diseases, hypotension,hypertension, tinnitus, pruritus, migraines, hearing difficulties,deficient intestinal motility, eating disorders, anorexia, obesity,locomotive disorders, diarrhea, cachexia, and urinary incontinence, orfor providing muscle relaxant, anticonvulsive, anaesthetic, diuretic,anti-natriuretic, or anxiolytic treatment, said method comprisingadministering to said patient a pharmaceutically effective amount of atleast one compound according to claim
 1. 46. A method according to claim45, wherein said compound is co-administered with an opioid analgesic orwith an anaesthetic.
 47. A process for producing a compound according toclaim 1 wherein R³═H, said process comprising the steps of: a) reactinga cyclohexane-1,4-dione protected with groups S¹ and S² according toformula II with a cyanide in the presence of a compound having theformula HNR⁰¹R⁰² to produce a protected N-substituted1-amino-4-oxocyclohexane carbonitrile compound corresponding to formulaIII

and then optionally acylating, alkylating or sulfonating at least oncein any sequence, or if at least one of R⁰¹, R⁰², and R⁰⁶=H protected bya protective group, eliminating at least one protective group and thenoptionally acylating, alkylating or sulfonating, or if at least one ofR⁰¹, R⁰², and R⁰⁶=H, introducing at least one H-protective group andthen optionally acylating, alkylating or sulfonating, b) contacting theaminonitrile of formula III with cyclopentadienyl cycloocta-1,5-dienecobalt (I) [cpCo(cod)] and irradiating under acetylene to produce acompound corresponding to formula IVa

and then optionally acylating, alkylating or sulfonating at least oncein any sequence, or if at least one of R⁰¹, R⁰², and R⁰⁶=H protected bya protective group, eliminating at least one protective group and thenoptionally acylating, alkylating or sulfonating, or if at least one ofR⁰¹, R⁰², and R⁰⁶=H, introducing at least one H-protective group andthen optionally acylating, alkylating or sulfonating, c) eliminating theprotective groups S¹ and S² from the compound of formula IVa to producea tetrasubstituted 4-aminocyclohexanone compound corresponding toformula IV

and then optionally acylating, alkylating or sulfonating at least oncein any sequence, or if at least one of R⁰¹, R⁰², and R⁰⁶=H protected bya protective group, eliminating at least one protective group and thenoptionally acylating, alkylating or sulfonating, or if at least one ofR⁰¹, R⁰², and R⁰⁶=H, introducing at least one H-protective group andthen optionally acylating, alkylating or sulfonating, d) reductivelyaminating the tetrasubstituted 4-aminocyclohexanone compound of formulaIVa with a compound having the formula HNR⁰⁴R⁰⁵ to produce a 2-pyridinecyclohexane-1,4-diamine compound corresponding to formula V

and then optionally acylating, alkylating or sulfonating in anysequence, or if at least one of R⁰¹, R⁰², R⁰⁴, R⁰⁵, and R⁰⁶=H protectedby a protective group, eliminating at least one protective group andthen optionally acylating, alkylating or sulfonating, or if at least oneof R⁰¹ R O₂, R⁰⁴, R⁰⁵, and R⁰⁶=H, introducing at least one H-protectivegroup and then optionally acylating, alkylating or sulfonating toproduce a compound corresponding to formula I, wherein R⁰¹ and R⁰² areindependently selected from the group consisting of H; H provided with aprotective group; C₁₋₈ alkyl and C₃₋₈ cycloalkyl, each being saturatedor unsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl and heteroaryl, each being mono- or polysubstitutedor unsubstituted; and aryl, C₃₋₈ cycloalkyl and heteroaryl, each bondedvia C₁₋₃ alkylene and each being mono- or polysubstituted orunsubstituted; or R⁰¹ and R⁰² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NR⁰⁶CH₂CH₂ or (CH₂)₃₋₆, where R⁰⁶ is selected fromthe group consisting of H; H provided with a protective group; C₁₋₈alkyl and C₃₋₈ cycloalkyl, each being saturated or unsaturated, branchedor unbranched, mono- or polysubstituted or unsubstituted; aryl andheteroaryl, each being mono- or polysubstituted or unsubstituted; andaryl, C₃₋₈ cycloalkyl and heteroaryl, each bonded via C₁₋₃ alkylene andeach being mono- or polysubstituted or unsubstituted; R⁰⁴ is selectedfrom from the group consisting of H; H provided with a protective group;and C₁₋₈ alkyl, saturated or unsaturated, branched or unbranched, mono-or polysubstituted or unsubstituted; R⁰⁵ is selected from the groupconsisting of H; H provided with a protective group; C₃₋₈ cycloalkyl,aryl and heteroaryl, each being unsubstituted or mono- orpolysubstituted; —CHR¹¹; —CHR¹¹—CH₂R; —CHR¹¹—CH₂—CH₂R;—CHR¹¹—CH₂—CH₂—CH₂R; —C(Y)R¹²; —C(Y)—CH₂R¹²; —C(Y)—CH₂—CH₂R¹² and—C(Y)—CH₂—CH₂—CH₂R¹², where Y═H₂, R¹¹ is selected from the groupconsisting of H and C₁₋₇ alkyl, saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted; and R¹² isselected from the group consisting of H, and C₃₋₈ cycloalkyl, aryl andheteroaryl, each being unsubstituted or mono- or polysubstituted; or R⁰⁴and R⁰⁵ together form a heterocyclic ring containing form 3 to 8 atoms,saturated or unsaturated and mono- or polysubstituted or unsubstituted;and S¹ and S² are independently selected from protective groups ortogether denote a protective group.
 48. A process according to claim 47,wherein the protective groups at H in at least one of R⁰¹, R⁰², R⁰⁴, R⁰⁵and R⁰⁶ are selected from the group consisting of alkyl, benzyl andcarbamates.
 49. A process according to claim 47, wherein the reductiveamination in step d) takes place in the presence of ammonium formate,ammonium acetate or NaCNBH₃.
 50. A process according to claim 47,wherein instead of the reductive amination with HNR⁰⁴R⁰⁵ in step d),compound IV is reacted with hydroxylamine and reduced after oximeformation.
 51. A process according to claim 47, wherein the irradiationin step b) lasts between 5 and 7 hours.
 52. A process according to claim47, wherein the irradiation in step b) takes place at room temperature.53. A process according to claim 47, wherein the irradiation in step b)takes place in a saturated acetylene atmosphere.
 54. A process accordingto claim 47, wherein the irradiation in step b takes place under aprotective gas.
 55. A process for producing a compound according toclaim 1 wherein R³═H, said process comprising the steps of: a)reductively aminating a cyclohexane-1,4-dione protected with groups S¹and S² according to formula II with a compound having the formulaHNR⁰⁴R⁰⁵ to produce a 4-aminocyclohexanone compound corresponding toformula VI

and then optionally acylating, alkylating or sulfonating at least oncein any sequence, or if at least one of R⁰⁴ and R⁰⁵=H protected by aprotective group, eliminating at least one protective group and thenoptionally acylating, alkylating or sulfonating, or if at least one ofR⁰⁴ and R⁰⁵=H, introducing at least one H-protective group and thenoptionally acylating, alkylating or sulfonating, b) reacting the4-aminocyclohexanone compound of formula VI with cyanide in the presenceof a compound having the formula HNR⁰¹R⁰² to produce a cyclohexanonenitrile compound corresponding to formula VII

and then optionally acylating, alkylating or sulfonating at least oncein any sequence, or if at least one of R⁰¹R⁰², R⁰⁴, R⁰⁵ and R⁰⁶=Hprotected by a protective group, eliminating at least one protectivegroup and then optionally acylating, alkylating or sulfonating, or if atleast one of R⁰¹, R⁰², R⁰⁴, R⁰⁵ and R⁰⁶═H, introducing at least oneH-protective group and then optionally acylating, alkylating orsulfonating, c) contacting the cyclohexanone nitrile compound of formulaVII with cyclopentadienyl cycloocta-1,5-diene cobalt (I) [cpCo(cod)] andirradiating under acetylene to produce a 2-pyridinecyclohexane-1,4-diamine compound corresponding to formula V

optionally acylating, alkylating or sulfonating at least once in anysequence, or if at least one of R⁰¹, R⁰², R⁰⁴, R⁰⁵ and R⁰⁶=H protectedby a protective group, eliminating at least one protective group andthen optionally acylating, alkylating or sulfonating, or if at least oneof R⁰¹, R⁰², R⁰⁴, R⁰⁵ and R⁰⁶=H, introducing at least one H-protectivegroup and then optionally acylating, alkylating or sulfonating toproduce the compound corresponding to formula I, wherein R⁰¹ and R⁰² areindependently selected from the group consisting of H; H provided with aprotective group; C₁₋₈ alkyl and C₃₋₈ cycloalkyl, each being saturatedor unsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; aryl and heteroaryl, each being mono- or polysubstitutedor unsubstituted; and aryl, C₃₋₈ cycloalkyl and heteroaryl, each bondedvia C₁₋₃ alkylene and each being mono- or polysubstituted orunsubstituted, or R⁰¹ and R⁰² together form a ring and denoteCH₂CH₂OCH₂CH₂, CH₂CH₂NRO⁶CH₂CH₂ or (CH₂)₃₋₆, where R⁰⁶ is selected fromthe group consisting of H; H provided with a protective group; C₁₋₈alkyl and C₃₋₈ cycloalkyl, each being saturated or unsaturated, branchedor unbranched, mono- or polysubstituted or unsubstituted; aryl andheteroaryl, each being mono- or polysubstituted or unsubstituted; andaryl, C₃₋₈ cycloalkyl and heteroaryl, each bonded via C₁₋₃ alkylene andeach being mono- or polysubstituted or unsubstituted; R⁰⁴ is selectedfrom the group consisting of H; H provided with a protective group; andC₁₋₈ alkyl, saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; R⁰⁵ is selected from the groupconsisting of H provided with a protective group; C₃₋₈ cycloalkyl, aryland heteroaryl, each being unsubstituted or mono- or polysubstituted;—CHR¹¹R²; —CHR¹¹—CH₂R¹²; —CHR¹¹—CH₂—CH₂R¹²; —CHR¹¹—CH₂—CH₂—CH₂R¹²;—C(Y)R¹²; —C(Y)—CH₂R¹²; —C(Y)—CH₂—CH₂R¹², and —C(Y)—CH₂—CH₂—CH₂R¹²,where Y═H₂; R¹¹ is selected from the group consisting of H, C₁₋₇ alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; and R¹² is selected from the groupconsisting of H, and C₃₋₈ cycloalkyl, aryl and heteroaryl, each beingunsubstituted or mono- or polysubstituted, or R⁰⁴ and R⁰⁵ together forma heterocyclic ring containing from 3 to 8 atoms, saturated orunsaturated; mono- or polysubstituted or unsubstituted, and S¹ and S²are independently selected from the group consisting of protectivegroups or together denote a protective group.
 56. A process according toclaim 55, wherein the protective groups at H in at least one of R⁰¹,R⁰², R⁰⁴, R⁰⁵ and R⁰⁶ are selected from the group consisting of alkyl,benzyl and carbamates.
 57. A process according to claim 55, wherein theirradiation in step c) lasts between 5 and 7 hours.
 58. A processaccording to claim 55, wherein the irradiation in step c) takes place atroom temperature.
 59. A process according to claim 55, wherein theirradiation in step c) takes place in a saturated acetylene atmosphere.60. A process according to claim 55, wherein the irradiation in step c)takes place under a protective gas.